Paclitaxel is a clinically effective chemotherapeutic agent approved for the treatment of various cancers. However, because paclitaxel has very low water solubility (˜10 μg/ml) which, due to a lack in suitable chemical functionality for salt formation, cannot be increased by pH adjustment, formulation of paclitaxel has proven difficult. As a result, most of the formulation work known in the art has been based on the use of co-solvents, surfactants and excipients (i.e., cyclodextrin) for intravenous (IV) formulations. Further, the oral bioavailability of paclitaxel has also been reported to be very low and as a result there is no oral formulation of paclitaxel on the market.
One of the commercially available intra-venous (IV) paclitaxel formulations is marketed under the trade name of Taxol® by Bristol-Myers/Squibb. Taxol® contains 6 mg/ml of paclitaxel, 527 mg/ml of a surfactant, (Cremophor EL, a polyethoxylated castor oil), and 49.7% (v/v) of absolute ethanol. This formulation requires a 5 to 20 fold dilution with either 5% dextrose or 0.9% NaCl solution which is then delivered by an intravenous infusion into the patient. Because of the low drug content in the Taxol formulation, a large volume of the formulation is administered to the patient in order to provide the required therapeutic doses (˜135-170 mg/m2). It is also worth noting that the amount of Cremophor EL necessary to deliver the required dose of paclitaxel in the Taxol formulation is considerably high (88 mg Cremophor EL per mg paclitaxel) and this vehicle has caused serious, life-threatening anaphylactoid reactions in animals and humans, even without paclitaxel. In addition, it has also been noted that that the Cremophor/ethanol formulation of paclitaxel precipitates upon dilution with infusion fluid and that fibrous precipitates are formed in some compositions when stored for extended periods of time. Additional information regarding disadvantages of paclitaxel compositions containing high concentrations of Cremophor may be found in U.S. Pat. No. 5,504,102 to Agharkar et al.
To alleviate the severe side-effects of the paclitaxel/cremophor formulations, patients are often required to receive premedication and/or prolonged paclitaxel infusion duration time of up to 24 hours. These measures, however, carry significant disadvantages. For example, the long infusion duration is inconvenient for patients, and is expensive due to the need to monitor the patients for the entire 6 to 24-hour infusion duration and the patient's prolonged stay in a hospital or treatment clinic. Similarly, premedication increases patient discomfort and increases the expense and duration of treatment. Moreover, such measures normally would not completely eliminate the side effects.
U.S. Pat. No. 5,641,803 to Canetta et. al. discloses a method of administering paclitaxel dosages of about 135 mg/m2 via infusions of less than 6 hours duration. This method requires pretreatment of the patients with steroids, antihistamines, and H2-receptor antagonists sufficient to prevent fatal anaphylactic-like reactions.
U.S. Pat. Nos. 6,136,846 and 6,319,943 disclose an oral formulation of paclitaxel which comprises paclitaxel, a solvent, and a pharmaceutically-acceptable, water-miscible solubilizer forming micelles, the solubilizer being selected from the group consisting of solubilizers having the general structures: R1 COOR2, R1 CONR2, and R1 COR2, wherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety and wherein the solubilizer is selected such that it does not have a pKa less than about 6. The concentration of paclitaxel in the composition disclosed in U.S. Pat. Nos. 6,136,846 and 6,319,943 is 5-20 mg/g.
U.S. Pat. No. 5,648,090 to Rahman et. al. discloses a liposomal-encapsulated paclitaxel or an anti-neoplastic derivative thereof that is used to effect a therapeutically enhanced method of treating cancer, and may be used advantageously in combination with hyperthermia. The liposomes confer enhanced stability and solubility characteristics to paclitaxel or derivatives thereof.
U.S. Pat. No. 5,424,073 to Rahman et. al. discloses a liposomal-encapsulated paclitaxel or an anti-neoplastic derivative thereof which comprises a liposome forming material, cardiolipin, paclitaxel and a pharmaceutically acceptable carrier. The liposome forming material is phosphatidyl choline, cholesterol, and the like and the liposomes formed thereby may have a positive, negative or neutral charge. The liposomes confer enhanced stability and solubility to paclitaxel or derivatives thereof.
U.S. Pat. No. 6,090,955 to Reszka et. al. discloses a liposome-encapsulated paclitaxel composition that consists of a high paclitaxel concentration with high stability and hence a high therapeutic effect. The invention involves the development of specific forms of paclitaxel encapsulation and the use of these, optionally in combination with other substances, in the treatment of various types of tumor. The liposome consists of a lipid, an amphiphillic material, a polymer and a carrier liquid. The liposome-encapsulated paclitaxel is characterized in that it is prepared by high-pressure homogenization or by aerosol formulation.
U.S. Pat. No. 5,415,869 to Straubinger et. al. discloses a pharmaceutical composition for use in treatment of cancer patients comprised of at least one taxane and a mixture of one or more negatively charged phospholipids and one or more zwitterion (i.e. neutral) phospholipids. This mixture entraps the taxane in what is believed to be a liposome. The mixture contains a ratio of negatively charged phospholipids to zwitterion phospholipids of 1:9 to 7:3. The paclitaxel is present in an amount of 1.5-8.0 mole percent taxane. The composition is in the form of particles having a size of 0.025 to 10 microns with substantially no taxane crystals. One of the negatively charged phospholipids is diphosphatidyl choline, i.e. cardiolipin.
U.S. Pat. No. 5,683,715 to Boni et. al. discloses liposomal taxane formulations where the liposomal lipid is a phosphatidylcholine; these formulations are useful for treating animals afflicted with cancers.
U.S. Pat. No. 5,728,687 to Bissery discloses pharmaceutical compositions having therapeutic synergy comprising paclitaxel or taxotere or analogues thereof combined with at least one other therapeutically useful substance for treating neoplastic diseases. The other therapeutic substance is selected from the group consisting of an alkylating agent, epidophylloptoxin, an anti-metabolite or a vinca alkaloid.
U.S. Pat. No. 6,096,331 to Desai et. al. discloses and claims compositions and methods that are useful for the in-vivo delivery of taxane, wherein the taxane is formulated with a polymeric biocompatible material such as human serum albumin. The compositions are substantially cremophor-free and a variety of neoplastic tumors are treatable thereby.
U.S. Pat. No. 5,908,835 to Bissery discloses anti-tumor compositions comprising paclitaxel, taxotere or their derivatives in combination with an anthacycline antibiotic, the combination having a synergistic pharmacological activity greater than the expected additive effect of its individual components.
U.S. Pat. Nos. 5,665,382 and 4,498,421 to Grinstaff disclose and claim pharmaceutical compositions in which an active agent is encapsulated within a polymer shell whose cross-sectional dimension is no greater than 10μ. The shell consists of a biocompatible material such as proteins, lipids, polysaccharides and polynucleic acids all of which possess sulfhydryl groups that are cross-linked to form the shell. The pharmaceutical agent is any one of a number of generically disclosed groups excluding anti-cancer compounds.
U.S. Pat. Nos. 5,916,596 and 5,439,686 to Desai et. al. disclose pharmaceutical compositions comprising emulsions of polymer-encapsulated pharmaceutical agents including protein encapsulated paclitaxel. The polymer is a protein, polysaccharide, polypeptide or polynucleic acid cross-linked by disulfide bonds. The emulsion is any one of a wide variety of organic solvents.
Accordingly, there exists a clear need for oral compositions of paclitaxel that are easy to prepare, contain a high concentration of paclitaxel but a low surfactant level, cause fewer side effects, have improved stability and have high oral bioavailability.